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Eur J Clin PharmacolDOI 10.1007/s00228-007-0454-6 Predictors of orphan drug approval in the European Union Harald E. Heemstra & Remco L. de Vrueh &Sonja van Weely & Hans A. Büller &Hubert G.M. Leufkens Received: 12 September 2007 / Accepted: 19 December 2007 Conclusion This study showed that experience of a Objective To encourage the development of drugs for rare company in developing orphan drugs is an important diseases, orphan drug legislation has been introduced in the predictor for subsequent authorisation of other orphan USA (1983) and in the EU (2000). Recent literature drugs. The same applies for existing (synthetic) molecules, discusses factors that may influence the development of for which much knowledge is available. Further research new orphan medicinal products in the EU. This study aims should be directed towards studying the quality of the to identify predictors for successful marketing authorisation clinical development program of those designated orphan of potential orphan drugs in the EU.
medicinal products not reaching approval status.
Methods A comparison between randomly selected author-ised and a matched sample of not-yet-authorised orphan Keywords Orphan drugs . Rare diseases .
drug designations has been performed. Determinants in the study included characteristics of the indication, of the productand of the sponsor. Data were collected from the publicdomain only.
Results Orphan drug approval was strongly associated withprevious experience of the sponsor in obtaining approval In Europe and the United States (USA) together, more than 55 for another orphan drug (OR=17.3, 95% CI=5.6–53.1).
million people suffer from a rare disease. It is estimated that Furthermore, existing synthetic entities compared to bio- approximately 5,000 to 7,000 rare diseases exist, and every technology products tended to have a higher likelihood of year about 250 new ones are described , This is partly reaching approval status (OR=3.9, 95% CI=0.9–16.6).
due to our continuously improving knowledge on diseasebiology and genomics, which allows more prevalent diseasesto be broken down into several rare diseases. In addition to H. E. Heemstra : H. G. M. Leufkens (*) this, new symptoms, mechanisms and aetiologies are Division of Pharmacoepidemiology and Pharmacotherapy, described in literature, representing more new diseases Utrecht Institute for Pharmaceutical Sciences,Faculty of Science, Utrecht University, As yet, for many rare diseases, no treatment is available P.O. Box 80.082, 3508 TB Utrecht, The Netherlands , ]. The high costs and risks of drug development, combined with difficulties in conducting clinical trials in small patient populations and the small market size, discourage the pharmaceutical industry from developing drugs for these rare diseases . Finding ways to bring R. L. de Vrueh S. van WeelySteering Committee on Orphan Drugs, drugs for rare diseases to patients is therefore an important P.O. Box 93245, 2509 AE The Hague, The Netherlands Consequently, several jurisdictions have put forward incentives to stimulate the development of drugs for rare Department of Paediatrics, Erasmus Medical Centre,P.O. Box 2040, 3000 CA Rotterdam, The Netherlands diseases. Following the successful Orphan Drug Act in the USA, the European Union (EU) introduced its Regulation indication may influence the perspectives on marketing on Orphan Medicinal Products in April 2000 ]. The authorisation, as the risk-benefit balance may be influenced systems have much in common, although a few differences by the degree of severity of specific disease classes. The exist. In the USA, drugs indicated for a maximum of objective of this study is therefore to identify predictors of 200,000 patients (equivalent to 7 patients per 10,000 successful marketing authorisation in the EU.
residents) are eligible for orphan drug designation. In theEU, an orphan designation will only be provided by theEuropean Commission if the product is intended for the diag- nosis, prevention or treatment of a life-threatening orchronically debilitating condition that affects fewer than 5 in Selection of candidate orphan medicinal products 10,000 patients. Moreover, the sponsor should establish thatthere exists no satisfactory method for the diagnosis, treatment The cohort of 386 designated orphan drugs and orphan or prevention of this condition, or if such exists, that the new drug candidates has been followed from the start of the EU product will be of significant benefit for those affected by that Regulation on Orphan Medicinal Products in April 2000.
We enrolled all designated orphan medicinal products with a Designated potential orphan drugs in the EU are entitled marketing authorisation by the European Commission up to 1 to several incentives, of which a market exclusivity of October 2006 in our analysis and compared these to a subset 10 years upon authorisation is the most important one ].
of the designated, but not yet authorised, orphan drugs. To Other incentives are direct access to the centralised avoid potential bias due to time-related differences in the procedure for European marketing authorisation, 50% fee probability of getting authorisation, for each authorised reductions for regulatory procedures and free scientific product, a random sample of up to two designated products advice during the development process [With this from the same time period (120 days before to 120 days after) designation procedure, the EU aims to stimulate bottom-up as the designation date of the authorised product was selected.
initiatives to further develop possible orphan drugs.
Authorised orphan drugs with multiple authorised indications Thus, an orphan drug designation system creates a ‘pre- (imatinib, sunitinib and dasatinib) were sampled to up to two screen’ of promising future orphan drugs. However, to be unapproved orphan drugs for each indication.
designated does not automatically mean an orphan drug willbe authorised for marketing. A recent study by Joppi pointed out that in April 2004, only 7.1% of the EU designatedpotential orphan drugs were approved for marketing, ques- To test our hypothesis, we collected data for each product tioning whether the incentives are sufficient to provide the on the indication, the product and the sponsor. Selection of European market with new orphan drugs [These data was limited to the public domain. Indication character- observations give strong impetus to the question of what istics included data on the type of disease and disease determines successful development and marketing author- prevalence for which the product is indicated. Product isation of an orphan drug. In other words: what makes an characteristics included data on the type of product, orphan designation result in an authorisation? A paper by proposed route of administration and previous approval or Dear argued that the US Orphan Drug Act is so successful designation of the molecule in other geographic regions than because of tax grants, which are not available in Europe [].
the EU. Sponsor characteristics included those details of the Other factors that have been suggested as relevant in terms of sponsor that may be indicative for demonstrating the favour- influencing the likelihood of approval are the potential of the ability of the product, including the size of the company, sponsor to carry out suitable clinical trials and the level of geographic region of drug development and experience of the patient involvement in the development process How- company with drug development. A full list of these variables ever, beyond these suggested factors, additional character- is shown in Table If available, EMEA definitions were istics may be of importance that have not been studied yet.
used for the classification of the subcategories and variables.
Since all products have to comply with the criteria of quality, safety and efficacy, we hypothesise that designated ), European Public Assessment Reports (EPARs), orphan medicinal products that have not (or not yet) sponsor websites, annual reports, press releases, and peer- obtained marketing approval therefore either have unfav- ourable characteristics or the sponsor of the product has notbeen able to show the favourability of the product characteristics. The latter can have multiple causes, includ-ing lack of experience or insufficient means for the clinical Characteristics of approved and unapproved orphan medic- development program. In addition to this, the type of inal products were compared using a univariate analysis.
Table 1 Overview of characteristics and definitions of designated 2006). To test whether any of the characteristics were mutually related, a multivariate model was used in which the characteristics with statistically significant crude ORswere compared using a backwards selection procedure.
Anti-infectives (J)Alimentary tract and metabolism (A) From the start of the EU Regulation on Orphan Medicinal Products (April 2000) up to 1 October 2006, 31 orphan medicinal products obtained marketing authorisation. One product (imatinib) has been authorised for four indications, and two other products (sunitinib and dasatinib) have been authorised for two indications, resulting in 36 approved orphan indications. A total of 60 designated (unauthorised) products were sampled to serve as controls. A small, Disease duration is generally over 3 months statistically significant difference in the stage of develop- ment between the two groups was found for those products for which clinical trials were initiated, but not yet completed (P=0.02), while this was not the case for products for which experimental model studies had been Innovative synthetic entities (EMEA list B), initiated or completed (P=0.08), and for products for which at least one clinical trial was completed ( Of the 31 authorised drug products, the majority (58.3%) were designated in the first 2 years of the EU Regulation on Orphan Medicinal Products (2000–2001). Twelve were ap- proved under exceptional circumstances, and one (sunitinib) had obtained conditional approval. Seven (22.6%) had received some form of protocol assistance or scientific advice from the EMEA. Of the 60 unauthorised designations, at least 43 (71.7%) were still in development in October 2006; of these, Large (>250 employees or 50M turnover) one had filed for market authorisation and another one had been authorised by November 2006. The development of six products could be classified as halted or on hold. For 11 Small (<50 employees or 5M turnover) and products, recent data on the development status were not Table shows an overview of the clinical characteristics of all 31 authorised orphan drugs for 36 indications, stratified by indication category and prevalence group of the indica- other medicinal products as of 1 Oct 2006(anywhere in the world) tion. Disease categories are based on ATC classes or combinations thereof that are also used by the Commission for Orphan Medicinal Products (COMP) of the EMEA [ The majority of the products were intended for oncologic and immunomodulatory diseases (ATC class L) (16, 44.4%) or alimentary and metabolic diseases (ATC class A) (9, 25.0%). In addition, most (24, 66.7%) authorised drugs ATC Anatomical Therapeutic Chemical, NCE new chemical entity, were intended for diseases with a prevalence lower than 1 in 10,000. Of the 16 approved oncology drugs, 13 (81%)were developed by large companies, 7 (44%) originated Odds ratios (OR) and 95% confidence intervals (CI) were from the USA and 5 (31%) from Switzerland. All these calculated for each characteristic in the three categories.
products were based on synthetic entities, and the majority, The outcome was defined as a successful EU marketing 12 (75%), were intended for oral use, whereas 4 (25%) authorisation within the study period (April 2000-October Table 2 Summary of characteristics of authorised orphan medicinal products from April 2000 to October 2006 ] Treatment of N-acetylglutamate synthetase (NAGS) deficiency Treatment of acute promyelocytic leukaemia Conditioning treatment prior to hematopoietic progenitor cell Treatment of primary and several secondary forms of pulmonary Treatment of glycogen storage disease type II (Pompe’s disease) Treatment of pulmonary arterial hypertension and chronic Treatment of mucopolysaccharidosis, type I Treatment of mucopolysaccharidosis, type VI (Maroteaux-Lamy Treatment of chronic pain requiring intraspinal analgesia Treatment of anthracycline extravasations Treatment of gastrointestinal stromal tumours (GIST) Treatment of familial adenomatous polyposis Treatment of acute lymphoblastic leukaemia Treatment of high-grade dysplasia in Barrett’s oesophagus Treatment of chronic iron overload requiring chelation therapy Treatment of pulmonary arterial hypertension and chronic Treatment of pulmonary arterial hypertension and chronic Treatment of malignant gastrointestinal stromal tumours Treatment of acute lymphoblastic leukaemia Treatment of dermatofibrosarcoma protuberans Treatment of acute lymphoblastic leukaemia The results of the univariate comparison between author- strongest for those characteristics that were related to the ised and not-yet-authorised orphan drugs are shown in Table experience of the sponsor with drug development. Previous For the categories of product characteristics and sponsor authorisation of an orphan drug by the sponsor was characteristics, a statistically significant association was associated with a 16-fold increase in the chance of author- observed for all the determinants except for the continent isation compared to no previous authorisation (OR=16.2, of drug development and for products with a previous 95% CI=5.5–47.4), whereas previous authorisation of other orphan designation outside the EU. The association was drugs and previous designation of another potential orphan Table 3 Results for the comparison between authorised and not-yet-authorised orphan medicinal products OR Odds ratio, 95% CI 95% confidence interval, ATC Anatomical Therapeutic Chemical, NA not applicable, OD orphan drug drug by the sponsor yielded odds ratios (95% CI) of 11.5 entities (NCEs)] such as imatinib was not statistically (3.2–42.2) and 8.0 (2.5–25.7) respectively. Furthermore, significant compared to biotechnology products (OR=2.0, previous authorisation outside the EU was also associated 95% CI=0.7–6.1), existing synthetic entities, such as arsenic with higher chances for authorisation in the EU (OR=4.0, trioxide and busulfan, were associated with higher chances 95% CI=1.1–14.5). Finally, the type of product is partly of market authorisation (OR=3.3, 95% CI=1.1–10.6).
associated with market authorisation. Although the associa- The results from the multivariate model, which assessed tion for innovative synthetic entities [e.g. new chemical whether any of the statistically significant characteristics Table 4 Multivariate analysis of predictors of marketing authorisation overcome this hurdle is EMEA’s dedicated SME office, which addresses the regulatory needs of SMEs [These incentives seem to be good steps forward to guide smallerand relatively inexperienced companies through the regu- latory maze in the development process. Although 80 procedures for protocol assistance had been completed by April 2005 ], we found that only 4 of the products that were approved in that period had obtained scientific advice or protocol assistance from the EMEA. Furthermore, of the OR Odds ratio, 95% CI 95% confidence interval, OD orphan drug 31 products authorised by October 2006, only 7 (22.6%) a Adjusted for significant variables in the univariate analysis (includ- received protocol assistance or scientific advice. In contrast, ing other ODs approved and type of product), followed by a 28 (77.8%) of the 36 approved orphan indications were backwards elimination procedure. Predictors in the table are those thatremained in the multivariate analysis developed by a company that had successfully broughtanother orphan drug to the market in Europe or the USA.
were related, are shown in Table . This model yielded two The development of imatinib is a good example of this. It independent predictors of successful marketing authorisa- was developed by a large company with extensive tion, namely the experience of the sponsor having other experience in developing and marketing medicinal products orphan medicinal products authorised and the type of product. The association was strongest for the authorisation The other independent predictor that was identified of other orphan products by a sponsor (OR=17.3, 95% CI= was the type of product. Although not significant, it shows 5.6–53.1). Moreover, we found a tendency toward an that the odds of authorisation for products based on existing association for the type of product, with an OR (95% CI) synthetic entities may be about four times higher compared of 3.9 (0.9–16.6) for existing synthetic entities compared to to biotechnological products. Only 6 of the 31 orphan drugs biotechnology products, while no association was observed approved in the EU up to October 2006 were of for innovative synthetic entities compared to biotechnology biotechnological origin; of these, 5 are used for enzyme products (OR=1.9, 95% CI=0.5–7.7).
replacement therapy for metabolic disorders. This finding isnot unexpected, as the development of existing syntheticentities into drug products is generally considered much more straightforward than the development of a biotechproduct. This group also includes orphan drugs based on This study reveals two independent characteristics of an existing approved therapies, such as celecoxib and sildena- orphan medicinal product that are associated with market- fil, for which development was only a matter of an ing authorisation: the experience of a company in develop- indication extension. This can be one of the reasons why ing drug products and the type of drug product in the relatively young European Regulation on OMPs has yielded such a high share of orphan drugs based on existing First, we showed that experience of a company in obtaining authorisation for orphan drugs was identified as In contrast to the EU, half of the biotechnological the most important predictor of market authorisation.
products approved in the USA in the period 1982–2002 Companies that have successfully brought an orphan drug were designated orphan drugs []. The US Orphan Drug to the market increase their odds of obtaining market Act is therefore frequently mentioned as one of the key authorisation for consecutive orphan drugs more than 17- factors that has stimulated the US biotech industry in its fold. These results are in line with opinions expressed by growth. Several of the world’s largest, US-based biotech many experts, however they are now supported by real data companies have in common that their first approved and emphasise the importance of an experienced partner in product was an orphan drug ]. This is illustrated by bringing a product to the market for small and medium- the fact that of the six approved biotech OMPs in the EU, sized enterprises (SMEs) whose experience is often limited five were originally developed in the USA. Since the US This observation is verified by the fact that many Orphan Drug Act was initiated nearly 25 years ago, those former SMEs with one or more approved orphan drugs companies have grown from SMEs to multinational have acquired the necessary experience by bringing on companies and have since acquired much more experience board experienced management at an early stage.
in drug development than the current European biotech The EMEA has addressed this issue by offering protocol companies with orphan drug designations in their portfolio.
assistance and scientific advice to sponsors of designated On the other hand, the small number of European biotech orphan drugs. Another important recent incentive to orphan drugs is compensated for by the relatively large number of orphan products based on existing synthetic small patient populations were really the key problem, we molecules. Examples of these are the products from the would see a larger share of orphan drugs for relatively French SME Orphan Europe, which are all based on common rare diseases in the EU, and only a very small existing molecules. This underlines that experience of a share of orphan drugs indicated for the very rare diseases.
company is even more important for the relatively more However, in our analysis, we found no association between complex biotechnological products. Since much clinical prevalence of the indication and market authorisation.
experience is already available, especially for existing Moreover, of the 36 indications for which an orphan synthetic molecules, this emphasises that, next to the medicinal product has been approved in the EU, 24 (67%) experience of a company, experience with a drug product had a prevalence of less than 1 per 10,000. In addition to this, Dear stated that, although small patient numbers may Except for products indicated for alimentary tract and hamper clinical trials for very rare diseases, it is not likely metabolism-related diseases (ATC class A), none of the to be a problem for more prevalent rare diseases [ characteristics related to the type of the indication showed a We need to consider other critical factors for the success statistically significant association with market authorisa- of the development of an orphan drug. The level of patient tion. This finding matched with our hypothesis that only the involvement may also influence successful development characteristics of the drug product itself or the development and subsequent authorisation of orphan drugs []. More- program of the sponsor determines the chances for market over, the registration dossiers of authorised orphan drugs authorisation. An interesting observation here is that the are often of poor quality, including inappropriate study number and type of products intended for oncologic design, lack of active comparators and inadequate end- indications suggest that the Regulation also provides points , ]. Although this criticism is primarily directed support for the development of the more classical antican- against orphan drugs already authorised, it is very possible cer drugs. In fact, this is one of the most successful niches that these dossiers are just the ‘tip of the iceberg’. If that is in orphan drug development in the EU so far.
the case, many orphan drugs will not reach the market Recent literature has discussed factors that influenced the because the sponsor will not be able to show evidence of development of orphan medicinal products in Europe [ favourable characteristics of the product due to the poor ]. One of the issues that has been raised in these quality of the dossier. Since this study has been based on papers is the absence of tax credits in the EU, compared to data from the public domain, several of these factors could the USA. The reason for this is that taxation is still a not be included, which is a limitation of the study. Future national affair in the EU, which is not regulated at the research to investigate the quality of the clinical develop- Community level. Although this is compensated for by a ment program of designated (unauthorised) orphan drugs longer period of market exclusivity in the EU and additional benefits on a national level [Joppi and Dear Another possible limitation of the study was the risk of suggest that this may yield fewer orphan drugs than in the biased outcomes due to possible differences in the stage of USA , While our analysis cannot fully produce a development of the products between the two groups that conclusive answer to this discussion, it gives some useful were compared. For this reason, the controls were randomly clues that the absence of tax credits alone is not the reason sampled from the same calendar period as the cases, so that for the lower number of approved products in the EU.
the chance that products would obtain approval was as Approximately one-third of the European orphan desig- equal as possible. Moreover, we compared the stage of nations were originally developed in the USA (data on file).
development at the time of the application for orphan However, in our analysis, no association was found designation based on data from the available Summaries of between the continent of drug development and market Opinion of the EMEA. Here it was shown that, although authorisation. These results suggest that the absence of tax slight differences existed, the two groups were roughly credits in the EU does not discourage companies from equal with regard to their stage of development at time of applying for an orphan designation in the EU.
Wästfelt described the problems of performing adequate- The relatively small number of products that have so far ly powered RCTs in small patient populations with rare been approved in the EU as compared to the enormous diseases, which are even more problematic in the multicul- number of rare diseases emphasises that the promises of the tural and multilingual setting of the EU compared to the European Regulation on OMPs have yet to be fulfilled.
USA []. Moreover, the USA has a successful infrastructure This paper has studied the characteristics of several of the for conducting trials in patient populations with rare early approved orphan drugs, the majority of them diseases, which is coordinated by the Rare Diseases authorised within the first 2 years of the Regulation. Now Clinical Research Network and supported by the Office of that the Regulation is about to enter its ninth year of Rare Diseases of the National Institutes of Health []. If the existence, the rate of orphan drug approval is gradually increasing and more and more orphan drugs are entering 4. Haffner ME (2006) Adopting orphan drugs-two dozen years of the market for the seriously needed treatment of patients treating rare diseases. N Engl J Med 354:445–447 5. Wästfelt M, Fadeel B, Henter JI (2006) A journey of hope: lessons learned from studies on rare diseases and orphan drugs. J Intern In conclusion, we have found that experience in the drug development process and development of already existing 6. Rinaldi A (2005) Adopting an orphan. EMBO Rep 6:507–510 (small) molecules are associated with market authorisation 7. EURORDIS (2005) Rare diseases: understanding this public health of orphan drug designations. The EMEA addresses this with several helpful incentives to support inexperienced 8. US FDA (1983) The Orphan Drug Act, Public Law, 97–141.
companies in their orphan drug development. There seems to be a steep learning curve for inexperienced companies.
9. Benzi G, Ceci A (1997) Drugs trying to get the parents: there will be incentives for the European scientific community to The incentives forthcoming from the European Regulation develop research in the field of the orphan drugs. Pharmacol Res on Orphan Medicinal Products seem to be helpful for companies developing orphan drugs, although the industry 10. Regulation (EC) No 141/2000 of the European Parliament and of has to ‘grow’ and acquire expertise on the specific the Council of 16 December 1999 on Orphan Medicinal Products.
Official Journal of The European Communities 2000 peculiarities of the orphan drug development process. The 11. Minghetti PM, Giudici EM, Montanari L (2000) A proposal to differences in orphan drug approvals between the EU and improve the supply of orphan drugs. Pharmacol Res 42:33–37 the USA may therefore be best explained by the maturity of 12. Dear JW, Lilitkarntakul P, Webb DJ (2006) Are rare diseases still the US pharmaceutical and biotech industry compared to orphans or happily adopted? The challenges of developing and usingorphan medicinal products. Br J Clin Pharmacol 62:264–271 Europe. In addition to this factor, other characteristics 13. European Commission (2006) Commission Staff Working Docu- related to the quality, safety and efficacy profile of a ment on the experience acquired as a result of the application of potential orphan drug certainly play a role. Especially with Regulation (EC) No 141/2000 on orphan medicinal products and regard to the possibilities of sponsors to demonstrate account of the public health benefits obtained. clinical evidence of the orphan drug under development.
14. Joppi R, Bertele V, Garattini S (2006) Orphan drug development is progressing too slowly. Br J Clin Pharmacol 61:355–360 15. EMEA (2005) COMP report to the commission in relation to Vrueh was supported by a grant from the Netherlands Organisation for article 10 of regulation 141/2000 on orphan medicinal products.
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